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New Tyrosine Kinase Inhibitor More Potent Than STI-571

New Tyrosine Kinase Inhibitor More Potent Than STI-571

December 01, 2002

MIAMI BEACH -The Bcr-
Abl tyrosine kinase inhibitor
PD173955 (PD17) binds to the target
ATP binding pocket even more
efficiently than STI-571 (imatinib
mesylate, Gleevec). It shows 15 to
20 times greater efficacy in chronic
myelogenous leukemia (CML) cell
lines because it can bind to either
open or closed activation loops.
Bayard D. Clarkson, MD, presented
the research at the Molecular Targets
and Cancer Therapeutics meeting,
sponsored by the American
Association for Cancer Research, National
Cancer Institute, and Europe-
an Organization for Research and
Treatment of Cancer (abstract 568).
"We basically pulled this compound
out of the literature, synthesized
it, and found that it worked,"
said Dr. Clarkson, Enid A. Haupt
Chair of Therapeutic Research and
head of the Hematopoietic Cell Kinetics
Laboratory at Memorial
Sloan-Kettering Cancer Center. The
MSKCC researchers collaborated
with Dr. John Kuriyan and other
Rockefeller University investigators
on the x-ray crystal structure work.
The initial translocation between
chromosomes 9 and 22 in CML produces
a BCR-encoded sequence fused
to a truncated c-Abl gene. The Bcr-
Abl protein encoded by this mutation
greatly increases c-Abl's tyrosine
kinase activity and causes the clinical
manifestations of CML. STI-517 produces
complete hematologic responses
in most cases of CML because it
binds to an ATP binding pocket and
blocks this process.
Dr. Clarkson's team set out to
find inhibitors of Bcr-Abl that might
be more effective than STI-571,
which is met by resistance in patients
whose CML is in blastic phase.
PD17 is more effective than STI-
571 at inhibiting cell lines containing
Bcr-Abl in vivo and at blocking
CML progenitor cells without inhibiting
normal progenitor cells. In
vitro assays showed that PD17 inhibited
fresh CML primary progenitor
cells in the low nanomolar
range. Dr. Clarkson said that PD17
is active and tolerable in mice at levels
that should be active in humans.
He presented x-ray crystal structures
of the catalytic domain of
c-Abl (Abl kinase) complexed with
either STI-571 or PD17. These
showed that STI-571 can bind to
the target site only when the 21-
residue activation loop of c-Abl is
in a closed configuration that resembles
substrate binding. PD17
binds when the activation loop is
open and resembles that of an active
kinase.
"Modeling shows that PD17 can
probably target c-Abl regardless of
the activation state it is in, but STI-
571 can only recognize the unique
downregulated form. The greater
potency of PD17 is probably due, at
least in part, to its ability to recognize
multiple states of the kinase.
We're not sure that is the entire reason,
however," Dr. Clarkson said.
Knowledge of the three-dimensional
structure of the Abl kinase
domain and how the specific inhibitors
differ in their binding properties
at a molecular level should allow
scientists to make rational
modifications to design and produce
even more potent and specific drugs
for treatment of leukemia and other
types of cancer, he said.
"I think that these tumors are
going to develop resistance even to
this drug [PD17], so we need more
than one molecular target. I think
that if we had three targets, as we do
in promyelocytic leukemia, there is
a good possibility that we could cure
these tumors," he said.
Dr. Clarkson also said that his
group has studied another
ParkeDavis (Pfizer) compound,
PD166326, that is about fourfold
more potent than PD17 in inhibiting
Abl kinase. It is now being studied
in CML mouse models.
"PD17 and PD16 are also much
more active than STI-571 against a variety
of human glioblastoma, sarcoma,
and neuroblastoma cell lines, but
higher concentrations are needed than
in the case of CML cells expressing
Bcr-Abl," Dr. Clarkson said.

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